The aging of the brain is a cause of cognitive decline in the elderly and the major risk factor for Alzheimer's and Parkinson's disease. An exciting recent development is the elucidation of a pattern of DNA damage in the aging human brain that is associated with reduced expression of genes that mediate synaptic plasticity, vesicular transport and mitochondrial function. Our finding of a "genetic signature" of brain aging that can be explained, at least in part, by oxidative DNA damage to vulnerable gene promoters provides a potentially novel conceptual framework for understanding how the brain ages. Moreover,preliminary transcript profiling of human blood lymphocytes shows that some age-regulated genes are common to blood and brain, suggesting that this process may be generally relevant to human aging. Preliminary studies also raise the possibility that age-related gene expression changes may be accelerated in Alzheimer's disease. These findings provide the basis for our hypothesis that DNA damage contributes to reduced expression of functionally important genes in human aging, and that this process may contribute to cognitive decline and vulnerability to Alzheimer's disease. The studies in this proposal will establish a genome-wide database of gene expression and DNA damage in aging human blood lymphocytesthrough the lifespan and compare it with the brain and kidney profiles to determine whether there is a conserved genomic program of human aging. Changes in age-regulated genes and DNA damage will be correlated with detailed neuropsychological indices obtained through the lifespan in subjects participating in the Religious Orders Study. Specific patterns of gene expression or DNA damage will be assessed that can predict change in global and specific cognitive abilities, and vulnerability to mild cognitive impairment and Alzheimer's disease, in subjects with up to 15 years of annual follow-up. These studies may provide insight into the pathogenesis of age-related cognitive decline, with potentially important diagnostic and therapeutic implications.